Sparc-driven p62-dependent mitochondrial oxidative stress exacerbates myocardial ischemia and is attenuated by ginsenoside CK

Myocardial ischemia (MI) remains a major global health challenge, with prevailing therapies inadequately addressing the critical link between metabolic dysfunction and structural remodeling. Ginsenoside CK (CK), a bioactive natural product, has shown cardioprotective effects, yet its precise molecular targets and mechanisms are not fully elucidated. This study employed an integrated multi-omics approach, combined with in vitro and in vivo validation and gene-editing techniques, to systematically investigate the pathogenesis of MI and the therapeutic basis of CK. Our findings indicate that the matricellular protein Sparc acts as a significant pathogenic driver in MI. We characterized the Sparc-p62 interaction axis, where Sparc directly interacts with the autophagy adaptor p62. This interaction triggers a series of harmful events, including severe disruption to the flux of mitochondrial autophagy, secondary mitochondrial dysfunction, the release of reactive oxygen species and the activation of inflammatory pathways. Ultimately, this leads to injury to the cardiomyocytes and abnormal extracellular matrix remodeling. CK was found to directly bind to Sparc, competitively inhibiting its role in overexciting p62. This effectively disrupts the pathogenic axis. Consequently, CK unblocks the degradation of inhibited mitochondrial autophagy streams, restores mitochondrial bioenergetics, and alleviates oxidative stress and inflammation. The results in a delay in the fibrosis process and a substantial improvement in cardiac function. The research identified the interaction between Sparc and p62 as a potential mechanism underlying MI injury and demonstrated the potential of CK to inhibit this pathway. It providing a scientific foundation for subsequent drug and mechanism research.